The Variances of Islet β-cell Function at Different Stages of Glucose Metabolism*

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1 3312 * ( ) 2 57 OGTT NGT IGT IFG+IGT T2DM IVGTT HOMA-IR [DI1= HOMA-β/HOMA-IR DI2=ΔI 30 /ΔG 30 /HOMA-IR DI3=MBCI IAI DI4= AIR 0-10 /HOMA-IR] AUC INS /HOMA-IR IGT IFG+IGT T2DM HOMA-IR P>0.05 NGT P<0.05 IGT IFG+IGT T2DM DI1 P<0.05 NGT IGT DI1 P>0.05 NGT IGT IFG+IGT T2DM DI2 DI3 DI4 P<0.05 IFG+IGT T2DM OGTTAUCINS/HOMA-IR P<0.05, NGT P<0.05 NGT IGT OGTTAUC INS /HOMA-IR P> IGT 1 IFG+IGT 1 2 T2DM 2 T2DM 3 1 T2DM 4 IFG+IGT 2 R587.1 A The Variances of Islet β-cell Function at Different Stages of Glucose Metabolism* YU Ting-ting, HU Yun, WANG Chun, HUANG Hong, TONG Guo-yu, YANG Dong-hui, ZHU Da-long (Department of Geriatrics, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, , China) ABSTRACT Objective: To guide the early diagnosis of type 2 diabetes mellitus (T2DM) by investigating the differences of insulin secretion and insulin sensitivity at differert stages from nomal glucose tolerance (NGT) to T2DM. Methods: A total of 57 Chinese adults were divided into NGT, isolated impaired glucose tolerance (IGT), combined impaired fasting glucose and impaired glucose tolerance (IFG plus IGT), and newly-diagnosed T2DM according to oral glucose tolerance test (OGTT), then were given to an intravenous glucose tolerance test (IVGTT) and insulin release test. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance (HOMA-IR); The islet β-cell function was evaluated by disposition indices[di1=homa-β/homa-ir, DI2=ΔI 30 /ΔG 30 /Homa-IR, DI3= MBCI IAI, DI4= AIR 0-10 /Homa-IR] and insulin area under curve of OGTT (AUC INS ) /Homa-IR. Results: HOMA-IR in IGT IFG plus IGT and newly-diagnosed T2DM groups were significantly higher than that of NGT (P<0.05), but there was no significant difference among IGT IFG plus IGT and newly-diagnosed T2DM (P>0.05). DI1 was gradually decreased from IGT through IFG plus IGT to newly-diagnosed T2DM (P<0.05) but there was no significant difference between NGT and IGT(P>0.05). DI2, DI3, DI4 were gradually decreased from NGT through IGT, IFG plus IGT to newly-diagnosed T2DM (P<0.05). but there was no significant difference between NGT and IGT (P>0.05). OGTTAUC INS /HOMA-IR was gradually decreased from IFG plus IGT to newly-diagnosed T2DM (P<0.05) but there was no significant difference between NGT and IGT (P>0.05). Conclusions:(1) Insulin resistance and the decline of first-phase, early-phase of insulin secretion existed in IGT at the same time. The decline of first-phase, early-phase of insulin secretion aggravated in IFG plus IGT, and impairment of basic-phase,second-phase of insulin secretion occurred, but the decrease of insulin sensitivity was not obvious. The dysfunction of all phase of insulin secretion existed in newly-diagnosed T2DM, but the decrease of insulin sensitivity was also not obvious. (2) β-cell function defection may play more important role during the development of T2DM. (3)Insulin sensitivity,firstphase and early-phase insulin secretion were predict factors of T2DM. (4) IFG plus IGT needed active intervention. Key words: Type 2 diabetes mellitus; Impaired glucose tolerance; Impaired fasting glucose; Nsulin sensitivity; Insulin secretion Chinese Library Classification(CLC): R587.1 Article ID: Document code: A * YKK cathytina_2000@sina.com zhudldr@gmail.com

2 3313 MBCI( β ) = (G 0 I 0 )/( G 60 + G ) Bergman 2 type 2 diabetes mellitus,t2dm (disposition index DI ) DI1= HOMA-β/ [1] β HOMA -IR DI2= I 30 / G 30 / HOMA-IR DI3= MBCI IAI DI4= [2-4] T2DM AIR 0-10 / HOMA -IR 4 β IR impaired fasting glucose IFG impaired glucose tolerance IGT IFG IGT IFG IGT T2DM ± x±s SPSS 13.0 IFG IGT T2DM IFG IGT one-way BMI 2 [5] IGT T2DM SNK [6] T2DM one-way β BMI P< OGTT 2.2 OGTT WHO NGT IVGTT 2 IGT 13 IFG+IGT 10 T2DM NGT IGT IFG+IGT T2DM 3 T2DM IGT NGT HOMA-IR P<0.05 (GAD) ( ICA) DI2 DI3 DI4 P<0.05 OGTTAUC INS /HOMA-IR (BMI) (WHR) g 05 DI1 DI2 DI3 DI4 OGTTAUC INS /HOMA-IR 10 75g P<0.05 IFG+IGT OGTT (IRT) min IFG+IGT IGT DI1 DI2 DI3 DI4 (TG) (TC) (HDL) P<0.05 IFG+IGT 1 (LDL) A(ApoA) B(ApoB) (BUN) (Cr) (UA) (GPT) (GOT) A1C (A1C) g 1 2 IVGTT IRT 3min 0min T2DM NGT HOMA-IR P< min IGT IFG+IGT P> BMI NGT 100% CV2.8% CV3.4% IGT DI1 DI2 DI3 DI4 OGTTAUC INS /HOMA-IR (Enzyme linked immunosorbent assay ELISA) NGT 78% 19% 35% 36% 79% IFG+IGT Mercodia CV1.7% CV3.5% β HOMA-IR 3 = (G0) (I0) / IR β 2 HOMAβ = 20 I 0 / (G 0-3.5) AIR 0-10 = I 0 +I 1 +I 2 +I 4 +I 6 +I 10 OGTT insulin area under curve, AUC I 2.1 NGT IGT IFG+IGT T2DM 1 IGT 1 2 IFG+IGT NGT HOMA-IR P<0. IGT T2DM NGT IGT IFG+IGT DI1 DI2 DI3 DI4 P<0.05, T2DM NGT 23% 7% 26% 15% 49% T2DM NGT 13% 4% 17% 7% 30% Homa-IR IAI [7] I 30 / G 30 = (I 30 -I 0 )/(G 30 -G 0 ) HOMA-β OGTTAUCI I 30 / G 30

3 3314 [8] MBCI OGTT120min β OGTT [9] [10] AIR OGTT (DI) β IR 2 IR β 1 x±s Table 1 Comparison of clinical characteristics among groups x±s NGT IGT IFG+IGT T2DM P values Number Gender(M/F) 7/5 7/6 5/5 12/10 - Age(years) 39.5±9.3bcd 50.4±8.4a 53.9±6.1a 53.7±12.2a BMI(kg/m 2 ) 22.7±2.1bcd 25.3±2.2a 24.8±3.1a 25.7±2.8a WHR 0.84±0.05bd 0.89±0.04a 0.87± ±0.05a SBP(mmHg) 116.3± ± ± ± DBP(mmHg) 77.5± ± ± ± TG(mmol/L) 1.3± ± ± ± TC(mmol/L) 4.4± ± ± ± HDL (mmol/l) 1.0± ± ± LDL (mmol/l) 2.3± ± ± ± Apo A(mmol/L) 1.1± ± ± ± Apo B(mmol/L) 0.8± ± BUN((mmol/L) 5.2± ± ± ± Cr(μmol/L) 77.9± ± ± ± UA(mmol/L) 359.4± ± ± ± GPT(U/L) 33.2± ± ± ± GOT(U/L) 28.1± ± ± ± A1C(%) 5.1±0.3d 5.8±0.4d 6.2±0.4d Note a P<0.05,vs NGT b P<0.05,vs IGT c P<0.05,vs IFG+IGT d P<0.05 vs T2DM. 8.3±1.8abc OGTT Fig.1 Plasma glucose and serum specific insulin levels at different time points during OGTT Note: a P<0.05, vs NGT; b P<0.05, vs IGT; c P<0.05, vs IFG+IGT;d P<0.05 vs T2DM. Diamonds, NGT; Squares, IGT; Triangles, IFG plus IGT; Circles, newly-diagnosed T2DM.

4 IVGTT Fig.2 Sserum specific insulin levels at different time points during IVGTT Note: a P<0.05, vs NGT; b P<0.05, vs IGT; c P<0.05, vs IFG+IGT; d P<0.05 vs T2DM. Diamonds, NGT; Squares, IGT; Triangles, IFG plus IGT; Circles, newly-diagnosed T2DM. 3 Fig.3 Comparision of islet β-cell function among groups Note: a P<0.05, vs NGT; b P<0.05, vs IGT; c P<0.05, vs IFG+IGT; d P<0.05 vs T2DM. [11] HOMA-IR HOMA-β HOMA-IR I 30 / G 30 IAI MBCI HOMA-IR AIR % BMI β β NGT IGT IFG+IGT T2DM IR HOMA-IR T2DM β T2DM HOMA-β β DI1 DI2 DI3 DI4 1 2 [12] OGTTAUC INS /HOMA-IR 3 IR β T2DM 1 IGT 2 [13] UKPDS 1 2 T2DM β 50% 1 2

5 [8] Hanson R L, Pratley R E, Bogardus C, et al. Evaluation of simple Kanat M indices of insulin sensitivity and insulin secretion foruse in epidemiologic studies[j]. Am J Epidemio, 2000, 151(2): IFG IGT IFG IGT [9],Bennett PH. OGTT 1 2 β Pima IGT [14] 5728 OGTT [J]., 2003, 19 1 : 8-12 IFG IGT Li Guangwei, Bennett PH. Possibility of evaluating islet β-cell function [15] IFG IGT by oral glucose tolerance test in epidemiological study on diabetes OGTTAUCINS IGT IFG+IGT NGT mellitus-analysis of euglycemic clamp study in 468 non 2diabetic Pima T2DM Indians[J]. Chin J Endocrinol Metab, 2003, 19(1): 8-12 OGTTAUC INS /HOMA-IR IFG+IGT T2DM [10] Cretti A, Lehtovirta M, Bonora E, et al. Assessment of beta-cell function IGT IFG+IGT 1 during the oral glucose tolerance test by a minimal model of insulin secretion [J]. Eur J Clin Invest, 2001, 31(5): β 2 [11] Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sens- T2DM β 2 OGTTAUC INS itivity and beta-cell glucose sensitivity from the response to intravenous glucose. [J]. J Clin Invest, 1981, 68(6): NGT IGT IFG+IGT IR β [12] Jensen C C, CnopM, HullR L, et al. Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic IGT IGT IR groups in the U. S[J]. Diabetes, 2002, 51(7): IGT HOMA-IR NGT IR IGT [13] UK Prospective Diabetes Study Group. U. K. prospective diabetes IGT 5.0± study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease[j]. Diabetes, 1995, 44(11): mmol /L 1 DI4 NGT mmol /L 1 [14] Kanat M, Mari A, Norton L, et al. Distinct β-cell Defects in Impaired [16] IGT DI2 NGT Fasting Glucose and Impaired Glucose Tolerance[J]. Diabetes, 2012, [17] 1 61(2): [18-20] 2 [15] Bi Y, Zeng L, Zhu D, et al. Association of β-cell function and insulin IFG+IGT A1C>6.0% sensitivity with fasting and 2-h plasma glucose in a large Chinese NGT 7%-49% IFG+IGT population [J]. Diabetes Obes Metab, 2012, 14(2): T2DM [16] Godsland IF, Jeffs JAR, Johnston DG. Loss of beta cell function as (References) [1] American Diabetes Association. Diagnosis and classification of diabetes mellitus[j]. Diabetes Care, 2008, 31(Suppl.1):S55-S60 [2] Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes[j]. Diabetologia, 2003, 46(1):3-19 fasting glucose increase in the non-diabetic range [J]. Diabetologia, 2004, 47(7): [17] Hanefeld M, Koehler C, Fuecker K, et al. Insulin secretion and insulin sensitivity pattern is different in isolated impaired glucose tolerance and impai red fasting glucose: the risk factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes study. [J]. Diabetes Care, [3] Saad MF, Knowler WC, Pettitt DJ, et al. A two-step model for development of non-insulin-dependent diabetes [J]. Am J Med, 1991, 90(2): , 26 (3): [18] Zethelius B, Hales CN, Lithell HO, et al. Insulin resistance, impaired early insulin response and insulin propeptides as predictors of the development [4] Nathan DM. Clinical practice. Initial management of glycemia in type 2 diabetes mellitus[j]. N Engl J Med, 2002, 347(17): [5] Abdul-Ghani MA, DeFronzo RA. Pathophysiology of prediabetes. [J]. Curr Diab Rep, 2009, 9 3 : [6] Matsue Y, Suzuki M, Nakamura R, et al. Prevalence and prognostic implications of pre-diabetic state in patients with heart failure [J]. Circ J, 2011, 75(12): of type 2 diabetes: a population-based, 7 year follow-up study in 70-year-old man[j]. Diabetes care, 2004, 70(6): [19] Zethelius B, Byberg L, Hales CN, et al. Proinsulin and acute insulin response independently predict type 2 diabetes mellitus in men-report from 27 years of follow-up study[j]. Diabetologia, 2003, 46(1):20-26 [20] Weyer C, Tataranni A, Bogardus C, et al. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening [7] Matthews DR, Hosker JP, RudenskiAS, et al. Homeostasis model assessment:insulin of glucose tolerance durin g each stage of type 2 diabetes resistance and beta-cell function from fasting plasma glu- development[j]. Diabetes Care, 2001, 24(1):89-94 cose and insulin concentrations in man [J]. Diabetologia, 1985, 28 (7):

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